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双酚A和4-壬基酚所致大鼠肝毒性作用机制的探讨

发布时间:2018-06-14 00:56  文章来源:笔耕文化传播

  本文选题:双酚A + 4-壬基酚 ; 参考:《华中科技大学》2015年博士论文


【摘要】:目的:肝脏毒性与氧化应激相关机制密切相关。相关研究表明内分泌干扰物如双酚A (bisphenol A, BPA)和4-壬基酚(4-nonylphenol,4-NP)可干扰哺乳动物肝脏功能。同时有研究报道BPA和4-NP可发挥类雌激素作用且具有肝毒性。本研究旨在研究BPA和4-NP暴露与肝脏相关效应生物标记物、肝脏抗氧化防御系统和肝脏毒性的关联性. 方法:48只SD雄性大鼠随机分成4组,每组6只,腹腔皮下注射2,10,50mg/kg(以玉米油为溶剂)的BPA和4-NP(实验组),同时以同等剂量的玉米油为溶剂对照。组。给药量为0.1ml/10g,每48小时注射1次,实验周期为30天。我们就BPA和4-NP对肝脏和血清中相关抗氧化酶(SGOT、SGPT. LDH和γ-GT)及肝损害的效应生物标记物的影响进行了相关研究:同时也研究了BPA和4-NP暴露所诱导凋亡、肝毒性和氧化应激相关基因表达的改变。此外,根据修正版BattsLudwig评分系统(评价坏死)和Brunt等制定的NASH分级和分期系统(评价脂肪变性、膨胀和小叶炎症),对肝损伤发病率和严重程度进行了定量分析。 结果:BPA处理组与对照组比较,大鼠体重和肝脏重量差异无统计学意义。4-NP处理组肝的绝对重量和相对重量与对照组比较,差异具有显著性。BPA处理组与4-NP处理组的丙二醛(MDA)和过氧化氢(H202)水平均增加,但BPA处理组的抗氧化酶过氧化氢酶(CAT)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-PX)水平均降低,且与对照组比较,差异均具有统计学意义(P0.05)。2mg/kg b.wt的4-NP处理组抗氧化剂CAT和GSH-Px活性显著性增加(P0.01),但10和50mg/kg b.wt的4-NP处理组CAT和GSH-Px活性显著性降低(P0.001)。4-NP处理组的血清SGOT、SGPT、LDH和γ-GT水平均增加,BPA处理组SGOT、SGPT和LDH的水平亦增加,但γ-GT水平减少。我们也对内分泌干扰物BPA和4-NP所诱导的细胞凋亡、肝毒性和氧化应激(OS)相关基因进行了研究。研究发现BPA可显著性增加氧化应激相关基因SODl、GPx和Txnrdl mRNA表达(P0.05或P0.01):结果亦显示BPA显著性降低Bcl-2mRNA表达,增加凋亡关键基因iNOS, TNF-α, Casp-3和Casp-9mRNA表达。4-NP可诱导氧化应激相关基因SOD1和GPx mRNA表达降低,与此同时,50mg/kg4-NP处理组的HSP70mRNA表达显著性增加(P0.05)。肝细胞凋亡可促进NAFLD进展,Fas/FasL、TNF-a和Caspase-9mRNA的激活在肝脂肪变性过程具有重要作用。此外,4-NP可显著性降低Bcl-2mRNA表达,同时诱导Bax mRNA表达增加。 结论我们的研究结果证实细胞凋亡、坏死和NAFLD进展与肝损害密切相关。此外,BPA所诱导的肝脏抗氧化系统的毒性反应可能导致细胞凋亡和坏死,引起长效肝毒性。同时,我们首次报道4-NP可干扰肝毒性效应相关基因异常表达,此改变与肝脂肪变性密切相关。
[Abstract]:Objective: liver toxicity is closely related to oxidative stress. Related studies have shown that endocrine disruptors such as bisphenol A (BPAA) and 4-nonylphenolophane (4-NPP) interfere with liver function in mammals. At the same time, it has been reported that BPA and 4-NP can play an estrogenic role and have hepatotoxicity. The aim of this study was to investigate the relationship between BPA and 4-NP exposure and liver related biomarkers, liver antioxidant defense system and liver toxicity. Methods Forty-eight Sprague-Dawley male rats were randomly divided into 4 groups, 6 rats in each group. BPA and 4-NPP (n = 6) were injected subcutaneously with 210g / kg (corn oil as solvent) and 4-NPP (experimental group), and the same dose of corn oil was used as solvent control. Group. A dose of 0.1 ml / 10 g was given once every 48 hours for 30 days. We studied the effects of BPA and 4-NP on liver and serum related antioxidant enzymes SGOTN SGPTs. The effects of LDH and 纬 -GT) and the effect biomarkers of liver damage were studied. The changes of apoptosis, hepatotoxicity and oxidative stress-related gene expression induced by BPA and 4-NP exposure were also studied. In addition, the incidence and severity of liver injury were quantitatively analyzed according to the revised BattsLudwig scoring system (evaluation of necrosis) and Brunt's Nash grading and staging system (evaluation of steatosis, swelling and lobular inflammation). Results there was no significant difference in body weight and liver weight between the control group and the control group. The absolute and relative weight of liver in the 4-NP treatment group was higher than that in the control group. The levels of MDA and H202) in BPA group and 4-NP group were increased, but the levels of antioxidant enzyme catalase (CATX), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were decreased in BPA treatment group. And compared with the control group, The activities of cat and GSH-Px increased significantly in 4-NP treatment group, but the cat and GSH-Px activities in 10 and 50mg/kg b.wt 4-NP groups were significantly lower than those in 4-NP treatment group, but the levels of serum SGOTSGPTPTLDH and 纬 -GT in 4-NP treatment group were significantly lower than those in 4-NP treatment group (P 0.001). 4-NP treatment group increased the levels of serum SGOTSGPTPTLDH and 纬 -GT in BPA-treated group, but the activities of cat and GSH-Px activity in 4-NP treatment group were significantly lower than those in 4-NP treatment group (P 0.001g 路4-NP group). The levels of SGPT and LDH in SGOT group were also increased. But the level of 纬 -GT decreased. We also studied genes associated with apoptosis, hepatotoxicity and oxidative stress induced by endocrine disruptors BPA and 4-NP. It was found that BPA could significantly increase the expression of oxidative stress-related genes (SODlGPx and Txnrdl mRNA) (P0.05 or P0.01). The results also showed that BPA significantly decreased the expression of Bcl-2 mRNA. Increasing the expression of iNOS, TNF- 伪, Casp-3 and Casp-9 mRNA. 4-NP could induce the decrease of SOD1 and GPX mRNA expression, while the HSP70 mRNA expression in 50 mg / kg 4-NP group increased significantly (P 0.05). Hepatocyte apoptosis can promote the progression of NAFLD. The activation of Fas-FasL mRNA, TNF-a and Caspase-9 mRNA plays an important role in the process of hepatic steatosis. In addition, 4-NP significantly decreased Bcl-2 mRNA expression and increased Bax mRNA expression. Conclusion our results confirm that apoptosis, necrosis and NAFLD progression are closely related to liver damage. In addition, the toxic response of liver antioxidant system induced by BPA may lead to apoptosis and necrosis, and cause long-term hepatotoxicity. At the same time, we report for the first time that 4-NP interferes with the abnormal expression of genes associated with hepatotoxicity, which is closely related to hepatic steatosis.
【学位授予单位】:华中科技大学
【学位级别】:博士
【学位授予年份】:2015
【分类号】:R114

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